The prevalence of HIV-related cognitive dysfunction remain high, and non-HIV-associated factors are now significant risk modifiers for cognitive impairment and alterations in brain structure. Perhaps most important factor related to the health of Americans with HIV disease is aging. The infection (and its consequences) appear to alter the normal age trajectories of structure or function in virtually all organ systems. In additon to the normal comorbidities that occur in individuals >50 years old, a chronic infection may result in significant burden to the brain, resulting in alterations in cognition and behavior. This concern is confounded by the fact that many individuals >50 years old currently alive with HIV disease were infected during the 1980/90s and endured years of uncontrolled or poorly controlled viral replication. During this five-year renewal period (AG034852), we will expand our current sample to 400 men with an additional 70 men >60 years old. They will undergo two scanning/testing sessions two years apart, resulting in a sample of 350 men with at least two scans, and as many as 280 men with four scans over 13 years. The brain imaging methodologies will assess the integrity of brain gray and white matter and the integrity of brain functional networks, tractography, metabolites, cerebral blood flow, and the integrity of the blood brain barrier. We will utilize these data, in combination with the 15-30 years of prior information from the Multicenter AIDS Cohort Study to evaluate the relative merits of a general conceptual model of the factors associated with the expression of cognitive and behavioral abnormalities in HIV Disease. We will complete detailed longitudinal analyses of the relationships between markers of subclinical vascular disease, inflammation, brain structure and cognition in the context of aging. We will specifically compare and contrast these relationships in HIV infected and uninfected men in order to address a series of linked hypotheses concerning possible mechanisms that may result in an apparent increase in the rate of cognitive dysfunction among HIV-infected individuals relative to age-matched controls.